Evaluation of stem cell-derived retinal pigment epithelial cells for retinal dise

干细胞来源的视网膜色素上皮细胞对视网膜疾病的评价

• 批准号: 8608528
• 负责人: MARTHA NEURINGER
• 金额: $ 42.88万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608528
• 关键词: Address; Adult; Age; Age related macular degeneration; Aging; Allografting; Animal Model; Animals; Autologous Transplantation; Biologic Characteristic; Biological; Biological Assay; Blindness; Cell Line; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Characteristics; Chronic; Clinic; Data; Degenerative Disorder; Disease; Dose; Engineering; Evaluation; Eye; Family suidae; Goals; Graft Rejection; Human; Immune; Immune response; Immune system; Immunologist; Immunology; Immunosuppression; In Vitro; Inflammation; Knowledge; Left; Light; Macaca mulatta; Measures; Metabolic; Methods; Mitochondria; Modeling; Molecular; Monkeys; Nonexudative age-related macular degeneration; Nutritional Support; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Photoreceptors; Physicians; Pluripotent Stem Cells; Primates; Production; Protocols documentation; Rattus; Recycling; Research Project Grants; Resources; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Retreatment; Risk; Rodent; Rodent Model; Scientist; Source; Stem cells; Structure; Structure of retinal pigment epithelium; Therapeutic Intervention; Time; Translational Research; Translations; Transplantation; Vision; Visual; Xenograft procedure; absorption; cell type; clinical practice; clinically relevant; disorder of macula of retina; embryonic stem cell; experience; immunogenicity; in vivo; induced pluripotent stem cell; innovation; insight; macula; nervous system disorder; nonhuman primate; novel; oxidation; pluripotency; prevent; public health relevance; retina transplantation; retinal rods; senescence; somatic cell nuclear transfer; success

DESCRIPTION (provided by applicant): Degenerative diseases of the retina are cumulatively the most common causes of untreatable blindness. These conditions, which include age-related macular degeneration and retinitis pigmentosa, are characterized by progressive loss of cells in the outer retina. Stem cells hold great promise for treating these diseases by repopulating cells that have been lost. A cell type that will be central to the success of this strategy is the retinal pigment epithelium (RPE). Recent technological breakthroughs make possible for the first time the production of recipient-specific donor cells through reprogramming of pluripotency in adult cells and directed differentiation. However, it is not known how RPE cells produced by these and other methods compare with respect to key biological characteristics, including immunogenicity and mitochondrial senescence, when transplanted to the healthy or diseased retina. These issues are critical to the potential use of such cells for retinal disease therapy. The goal of this proposal is to study the functionality of RPE cells generated from experimentally induced pluripotent stem cells in vitro and after transplantation to the rodent or nonhuman primate retina, including their immunogenicity and their ability to rescue visual loss in a rodent model of retinal degeneration. The project will make innovative use of unique resources, including allograft and autograft stem-cell-derived rhesus monkey RPE cell lines and a naturally-occurring nonhuman primate model of macular disease. The proposal has three specific aims: 1) To generate rhesus macaque RPE cells from three sources of pluripotent stem cells--embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (SCNT- ESCs), and induced pluripotent stem (iPS) cells--and evaluate their function in arresting visual decline in the RCS retinal degeneration model. 2) To investigate the immunology of these RPE cell types transplanted as allograft or autografts into the retina of adult rhesus monkeys and after retreatment of the same eye or fellow eye. 3) To characterize the differences in immune response between young and senescent rhesus monkeys, including those with age-related maculopathy which parallels intermediate human AMD. This translational research project will provide information key to the success of cell therapy in the retina. It will provide insights as to the most appropriate cell source to repopulate lost retinal cells with the aim of preserving or restoring vision, and will generate novel data on the immune response to such therapeutic intervention and the best approach to avoid graft rejection. The proposal will address these issues in an animal model with an eye and immune system that most closely resembles that of humans and in a manner closely mirroring potential clinical practice.

描述（由申请人提供）：视网膜的退化性疾病累计是最常见的不可治疗失明的原因。这些疾病包括与年龄相关的黄斑变性和色素性视网膜炎，其特征是外视网膜中细胞的逐渐丧失。干细胞通过重新流传丢失的细胞来治疗这些疾病有很大的希望。视网膜色素上皮（RPE）将是该策略成功的核心细胞类型。最近的技术突破使得通过重新编程成人细胞中的多能性并定向分化，这是第一次成为受体特异性供体细胞的产生。但是，当移植到健康或患病的视网膜时，这些和其他方法与关键生物学特征（包括免疫原性和线粒体衰老）相比，尚不清楚这些方法与其他方法相比如何。这些问题对于潜在的这种细胞用于视网膜疾病疗法至关重要。该提案的目的是研究由实验诱导的多能干细胞在体外和移植到啮齿动物或非人类灵长类动物视网膜后产生的RPE细胞的功能，包括其免疫原性以及它们在视网膜变性模型中挽救视觉损失的能力。该项目将创新使用独特的资源，包括同种异体移植和自体移植源源自源自的恒河猴RPE细胞系以及天然的黄斑疾病非人类灵长类动物模型。该提议具有三个具体的目的：1）从三个多功能干细胞的三个来源产生猕猴的RPE细胞 - 胚胎干细胞（ESC），通过体细胞核转移（SCNT-ESC）得出的ESC，并诱导多能干细胞（IPS）细胞（IPS）细胞（IPS）细胞 - 并评估它们在rc neTrical neTrics neTrics neTrics neTrics nitical nitical nitical nitical nitical nitical nitical nitic secennical niminal nitical nitic scornical scornical swornical septienal septiminal snectial模型中的功能。 2）研究这些RPE细胞类型的免疫学以同种异体移植或自体移植到成年恒河猴的视网膜以及同一只眼睛或同伴眼的后退后。 3）表征年轻和衰老恒河猴之间免疫反应的差异，包括那些与年龄相关的刺激症，与人类AMD相称。这个翻译研究项目将为视网膜中细胞疗法成功提供信息关键。它将提供有关最合适的细胞源以保存或恢复视力的目的，以重新填充丢失的视网膜细胞的见解，并将生成有关这种治疗干预的免疫反应的新数据，以及避免移植抑制的最佳方法。该提案将通过眼睛和免疫系统在动物模型中解决这些问题，最类似于人类的问题，并以一种紧密反映潜在的临床实践的方式。